Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures: ##STR1##
have been found to exert microtubule-stabilizing effects similar to paclitaxel (TAXOL.RTM.) and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Angew. Chem. Int. Ed. Engl., Vol. 35, No.13/14, 1567-1569 (1996).
Derivatives and analogs of Epothilones A and B have been synthesized and have been used to treat a variety of cancers and other abnormal proliferative diseases.
Such analogs are disclosed in Hofle et al., Angew. Chem. Int. Ed. Engl., 35, No.13/14 (1996); WO93/10121 published May 27, 1993 and WO97/19086 published May 29, 1997; and Nicolaou et al., Angew Chem. Int. Ed. Engl., Vol. 36, No. 19, 2097-2103 (1997); and Suet al., Angew Chem. Int. Ed. Engl., Vol. 36, No. 19,2093-2096 (1997).
For reasons of stability, it would be desirable to convert the epoxide moiety of Epothilones A and B to their corresponding aziridine form. However, conventional methods of affecting this conversion, such as the methods of R. Zamboni and J. Rokach, Tetrahedron Letters, 331-334 (1983); and Y. Ittah et al., J. Org. Chem., 43, 4271-4273 (1978), result in a molecule having an opposing stereoconfiguration.
Applicants have now found a process for synthesizing epothilones that retains the stereoconfiguration of the starting material.